Prognostic significance of tumor genotypes and CD8+ infiltrates in stage I-III colorectal cancer

Fountzilas, Elena; Kotoula, Vassiliki; Tikas, Ioannis; Manousou, Kyriaki; Papadopoulou, Kyriaki; Poulios, Christos; Karavasilis, Vasilios; Efstratiou, Ioannis; Pectasides, Dimitrios; Papaparaskeva, Kleo; Varthalitis, Ioannis; Papatsibas, George; Chrisafi, Sofia; Glantzounis, Georgios K.; Psyrri, Amanda; Aravantinos, Gerasimos; Koliou, Georgia-Angeliki; Koukoulis, George Κ.; Pentheroudakis, George; Fountzilas, George

doi:10.18632/oncotarget.26256

Cited by 17 publications

(18 citation statements)

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“…Adaptive intratumor immunity can contribute to tumor elimination or progression. Several preclinical and clinical studies have suggested that increased CD8 + T cell infiltration is correlated with a better prognosis for CRC patients [1][2][3][4]. Decreased CD8 + T cell density has been shown in advanced-stage CRC patients and those with nodal metastasis [5].…”

Section: Introductionmentioning

confidence: 99%

Th17 cells inhibit CD8+ T cell migration by systematically downregulating CXCR3 expression via IL-17A/STAT3 in advanced-stage colorectal cancer patients

Wang

Lian

et al. 2020

J Hematol Oncol

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Background: CD8 + T cell trafficking to the tumor site is essential for effective colorectal cancer (CRC) immunotherapy. However, the mechanism underlying CD8 + T cell infiltration in colorectal tumor tissues is not fully understood. In the present study, we investigated CD8 + T cell infiltration in CRC tissues and the role of chemokinechemokine receptor signaling in regulation of T cell recruitment. Methods: We screened chemokines and cytokines in healthy donor and CRC tissues from early-and advancedstage patients using multiplex assays and PCR screening. We also utilized transcription factor activation profiling arrays and established a xenograft mouse model. Results: Compared with tumor tissues of early-stage CRC patients, CD8 + T cell density was lower in advanced-stage tumor tissues. PCR screening showed that CXCL10 levels were significantly increased in advanced-stage tumor tissues. CXCR3 (the receptor of CXCL10) expression on CD8 + T cells was lower in the peripheral blood of advancedstage patients. The migratory ability of CD8 + T cells to CXCL10 depended on CXCR3 expression. Multiplex arrays showed that IL-17A was increased in advanced-stage patient sera, which markedly downregulated CXCR3 expression via activating STAT3 signaling and reduced CD8 + T cell migration. Similar results were found after CD8 + T cells were treated with Th17 cell supernatant. Adding anti-IL-17A or the STAT3 inhibitor, Stattic, rescued these effects in vitro and in vivo. Moreover, survival analysis showed that patients with low CD8 and CXCR3 expression and high IL-17A levels had significantly worse prognosis. Conclusions: CD8 + T cell infiltration in advanced-stage tumor was systematically inhibited by Th17 cells via IL-17A/ STAT3/CXCR3 axis. Our findings indicate that the T cell infiltration in the tumor microenvironment may be improved by inhibiting STAT3 signaling.

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Section: Introductionmentioning

confidence: 99%

Th17 cells inhibit CD8+ T cell migration by systematically downregulating CXCR3 expression via IL-17A/STAT3 in advanced-stage colorectal cancer patients

Wang

Lian

et al. 2020

J Hematol Oncol

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“…Cut-offs for protein markers were selected based on previously published studies (15)(16)(17)(18)(19)(20)(21). Evaluation of CD8 as intratumoral and stromal infiltrates was performed as previously described (22,23).…”

Section: Methodsmentioning

confidence: 99%

Prognostic Biomarkers in Early-stage Gastric Adenocarcinoma Treated With Adjuvant Chemoradiotherapy

Pectasides

Chatzidakis

Kotoula

et al. 2020

Cancer Genomics Proteomics

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Background/Aim: Early-stage gastric cancer has a high risk of recurrence, despite trimodality therapy with surgery, chemotherapy and radiation. To improve patient selection for adjuvant chemoradiotherapy, we evaluated the prognostic significance of immunohistochemical and genetic biomarkers in patients with resected gastric adenocarcinoma. Patients and Methods: Tumors from 119 patients were subjected to immunohistochemistry for 12 protein biomarkers, as well as next-generation sequencing. Clinical and biomarker data were available for 91 patients. Results: EBV-positive tumors and tumors with mutations had higher intratumoral CD8 tumor-infiltrating lymphocyte density (p=0.009 and p=0.017, respectively). PIK3CA mutations were correlated with VEGFA overexpression (p=0.042), while KRAS mutations and HER2 expression were mutually exclusive (p=0.036). PTEN expression univariately confirmed longer overall survival (HR=0.27; p=0.046), while there was a trend between the presence of KRAS mutations and inferior disease-free and overall survival. Conclusion: PTEN protein expression and KRAS mutations may predict disease outcome in early-stage gastric cancer. These results need to be further validated in larger cohorts. Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related mortality worldwide (1). Patients with stage I disease treated with gastrectomy have a 5-year survival rate of approximately 65%, whereas patients with more advanced disease have poorer outcomes with a 5year survival rate of 30% (2, 3). Complete surgical resection is required to cure gastric cancer (4). However, given the high recurrence rate after surgery, additional therapeutic approaches have been explored. These therapeutic strategies include 277 This article is freely accessible online.

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“…Genotyping data from 3,084 tumors were retrieved from 14 NGS datasets obtained from 2013 to 2017 in the context of HeCOG translational projects [7][8][9][10][11][12][13][14][15]. Eight tumor types were genotyped on the basis of tissue sample availability, research interests of the respective investigators, and funding opportunities: breast, colorectal, pancreatic, nasopharyngeal, glioma, gastric, biliary, and ovarian.…”

Section: Ngs Genotypingmentioning

confidence: 99%

“…HeCOG has previously investigated the genomic profiles of different tumor types using cancer-specific panels designed on the basis of available published data [7][8][9][10][11][12][13][14][15]. From 2013 to 2017, NGS was performed in the Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki, to assess clinically relevant molecular alterations in patients with cancer.…”

Section: Introductionmentioning

confidence: 99%

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Pathogenic mutations and overall survival in 3,084 patients with cancer: the Hellenic Cooperative Oncology Group Precision Medicine Initiative

et al. 2020

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Copyright: Fountzilas et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACTBackground: We evaluated the association between pathogenic mutations and overall survival (OS) in patients with cancer referred to Hellenic Cooperative Oncology Group-affiliated Departments.Patients and methods: Patients referred from 12/1980 to 1/2017 had molecular testing (for research) of archival tumor tissue collected at the time of first diagnosis (non-metastatic, 81%; metastatic, 19%). Tumor-specific gene panels (16-101 genes) were used to identify pathogenic mutations in clinically relevant genes. NGS genotyping was performed at the Laboratory of Molecular Oncology, Aristotle University of Thessaloniki. Annotation of mutations was performed at MD Anderson Cancer Center.Results: We analyzed 3,084 patients (median age, 57 years; men, 22%) with sequencing data. Overall, 1,775 (58% of 3,084) patients had pathogenic mutations. The median follow-up was 7.52 years (95% CI, 7.39-7.61). In patients with nonmetastatic tumors, after stratification by tumor type, increasing age, higher grade, and histology other than adenocarcinoma were associated with shorter OS. OS was also shorter in patients with pathogenic TP53 (HR=1.36; p<0.001), MLL3 (HR=1.64; p=0.005), and BRCA1 (HR=1.46; p=0.047) mutations compared to wild-type genes. In multivariate analyses, independent prognostic factors predicting shorter OS were pathogenic mutations in TP53 (HR=1.37, p=0.002) and MLL3 (HR=1.50, p=0.027); increasing age (HR=1.02, p<0.001); and increasing grade (HR=1.46, p<0.001). In patients with metastatic cancer, older age and higher grade were associated with shorter OS and maintained their independent prognostic significance (increasing age, HR=1.03, p<0.001 and higher grade, HR=1.73, p<0.001).Conclusions: Analysis of molecular data reveals prognostic biomarkers, regardless of tissue or organ of origin to improve patient management.

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Prognostic significance of tumor genotypes and CD8+ infiltrates in stage I-III colorectal cancer

Cited by 17 publications

References 51 publications

Th17 cells inhibit CD8+ T cell migration by systematically downregulating CXCR3 expression via IL-17A/STAT3 in advanced-stage colorectal cancer patients

Th17 cells inhibit CD8+ T cell migration by systematically downregulating CXCR3 expression via IL-17A/STAT3 in advanced-stage colorectal cancer patients

Prognostic Biomarkers in Early-stage Gastric Adenocarcinoma Treated With Adjuvant Chemoradiotherapy

Pathogenic mutations and overall survival in 3,084 patients with cancer: the Hellenic Cooperative Oncology Group Precision Medicine Initiative

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